Parkinson's disease (PD) is a devastating neurodegenerative disease which affects approximately 1 million people in this country. The chief symptoms include advancing slowness of movement (bradykinesia), tremor, rigidity, and postural imbalance. PD involves degeneration of the neurons that make dopamine, a chemical necessary for normal brain function. The diagnosis is entirely clinical: there are no routine laboratory tests available that can establish the diagnosis with certainty. PD has been considered to be an acquired disorder of unknown etiology. Treatment until 1989 has been entirely symptomatic - treating the symptoms but not the root cause of the disease. Very recent research has identified an enzyme defect in platelet mitochondria of patients with Parkinson's disease. The discovery of this defect in complex I activity suggests new investigative and therapeutic strategies, but first it is important to confirm the finding in a larger number and broader range of patients. This project proposes to examine platelet mitochondrial enzyme activity in: (1) a larger group of patients with typical Parkinson's disease (Is this enzyme assay sensitive?); (2) patients with "parkinson-plus" disorders, who have similar symptoms but also additional signs of central nervous system degeneration (Is this enzyme assay specific?); (3) first degree (blood) relatives of patients with PD (Does the enzyme defect appear to be inherited via the mitochondria (maternal) or is it autosomal dominant with reduced penetrance (the trait may be inherited from either parent, but not all who inherit it get sick?); and (4) healthy, age-matched controls. Two other enzyme activities will also be studied as a control for assessing the overall quality of the isolated platelet mitochondria. Because of large quantity of platelets is required for these special enzyme activities, these will be obtained by plateletpheresis, in which blood is removed from the body, the platelets are separated out, and the remainder of the blood is returned to the volunteer. Although platelets have not been recognized to have functional defects in patients with PD, this project will address this question by screening many patients with PD with functional tests (e.g., rate of aggregation, response to activators) performed on a small sample of peripheral blood obtained in the routine manner. This research should establish the range of complex I activity in each disorder and the sensitivity and specificity of this finding. Family studies will establish the occurrence and pattern of inheritance. Platelet functions studies will establish whether these widely-available tests could be used for screening persons at-risk or those with a questionable diagnosis. Although development of a diagnostic test would be a major clinical advance, the more important potential result of this work would be to point the way to new therapeutic strategies. Experimental therapeutics are under way in other genetic diseases to replace or stimulate defective enzymes; such a strategy could also be pursued for PD.